Are You Sure the Patient Has Hypogonadism?

Male hypogonadism is a clinical syndrome resulting from inadequate testosterone and/or sperm production from the testis. The presence and severity of the clinical manifestations of hypogonadism depend on the degree, duration, and timing of onset. A careful history, medication review, physical examination, and laboratory evaluation are essential to establish the diagnosis and underlying cause(s).

High risk medications, especially if use is prolonged (e.g., long-acting opioids, high-dose glucocorticoids)

Infertility

Fragility fracture, low BMD

Etiologies of Hypogonadism

Causes of hypogonadism may be separated into diseases of the testis (primary), and diseases of the hypothalamic-pituitary axis (secondary). Diseases of the testis may be further subdivided into combined defects in hormone production and spermatogenesis, and isolated defects in spermatogenesis.

Causes of primary hypogonadism

Combined defects in hormone production and spermatogenesis

Congenital/developmental disorders

Klinefelter syndrome (XXY karyotype, most common cause of primary hypogonadism)

Aging is not a cause of hypogonadism per se. Although serum testosterone levels decline with age, the decline is typically within the normal range. The increased incidence of hypogonadism in older men is largely attributed to the increased incidence of medical comorbidities.

What Else Could the Patient Have?

The differential diagnosis of hypogonadism includes other disorders that may cause sexual dysfunction (poor libido, erectile dysfunction, disorders of orgasm or ejaculation) or infertility. Because many of the symptoms of hypogonadism are nonspecific, and many of these disorders can directly cause sexual dysfunction along with hypogonadism, a careful history is essential.

Diagnosis of Hypogonadism: Key Laboratory and Imaging Tests

The diagnosis of hypogonadism requires consistent clinical signs and symptoms of testosterone deficiency in the setting of an unequivocally low fasting morning (ideally, 8-9 a.m.) serum total testosterone by a reliable assay. Specific attention should be paid to the normative ranges since they differ considerably amongst assays. Low testosterone levels should be confirmed with repeat fasting morning measurements due to the following observations:

The prevalence of low testosterone levels alone without symptoms or signs is much higher than the prevalence of the clinical syndrome,

Glucose administration and meals suppress serum testosterone levels,

Serum testosterone levels exhibit a circadian rhythm and the normal ranges of most assays were generated from morning values. Levels may decline as much as 25% by 8 p.m., although this decline is less prominent as men age,

15% of young healthy men may have a sub-normal testosterone level over the course of a day, and

Up to 35% of men with a mildly low serum testosterone level will have a normal level on repeat testing.

Diagnosis of hypogonadism is challenging since there is no universally accepted threshold serum testosterone level below which symptoms and increased morbidity/mortality have been consistently demonstrated. It's likely that various target tissues have unique thresholds for manifesting symptoms of androgen deficiency, with inter-individual variability due to varying androgen receptor sensitivity and modifying factors such as age-of-onset, duration, and comorbidities. This uncertainty is magnified by variability in assay methodology.

The majority of circulating testosterone is bound to sex-hormone binding globulin (SHBG) and albumin, with <3% of the total in circulation as free testosterone. Although bound-testosterone has traditionally been thought to be inactive, recent data suggest certain tissues may respond to SHBG-bound testosterone, and the relationship between each testosterone compartment is sufficiently complex and dynamic to require caution in interpreting ex vivo specimens that reflect a single point in time.

In men with borderline total testosterone values, or where a derangement of protein quantity or binding is suspected, measurement of free testosterone should be considered. Quantitative or qualitative abnormalities in protein binding may be seen in the following conditions:

Increased SHBG

Advancing age

Hepatitis, cirrhosis

Hyperthyroidism

HIV infection

Drugs, including anticonvulsants, estrogens

Decreased SHBG

Obesity

Diabetes

Hypothyroidism

Nephrotic syndrome or protein-losing enteropathy

Acromegaly

Drugs, including glucocorticoids, progestins, androgens

Although automated total testosterone assays are widely available and acceptably accurate, free testosterone assays are less reliable and are best performed at a reference laboratory using equilibrium dialysis methods (gold standard). Most local laboratories use testosterone analog-based immunoassays that do not accurately detect free testosterone. Free testosterone may also be calculated using total testosterone, SHBG, and albumin concentrations, however the accuracy of the calculation is dependent upon the quality of the individual assays. "Bioavailable" testosterone refers to the sum of free testosterone and testosterone bound to albumin (less tightly bound compared to SHBG) which is theoretically available after disassociation to bind to target tissues. Bioavailable testosterone may be directly measured by ammonium sulfate precipitation at a reference laboratory, or calculated similarly to free testosterone with acceptable accuracy.

Serum testosterone levels should not be measured during acute illness since transient secondary (and occasionally, primary) hypogonadism are frequently observed in this setting along with derangements in protein binding; the degree of hypogonadism is directly related to the severity of illness.

After confirming low morning serum total testosterone levels, laboratory evaluation with pituitary gonadotropins should be sought to establish the level of pathology in the hypothalamic-pituitary-testicular axis. LH and follicle-stimulating hormone (FSH) are elevated in primary (hypergonadotropic) hypogonadism, and are low or inappropriately normal in secondary (hypogonadotropic) hypogonadism. Isolated FSH elevations may be seen in isolated defects of spermatogenesis due to the loss of feedback inhibition from inhibin B, an important product of Sertoli cells in the seminiferous tubules. A careful history and physical examination can provide clues to the underlying cause and help guide additional testing.

In men with primary hypogonadism, further evaluation should include:

Karyotype analysis - Karyotype of peripheral leukocytes will evaluate for Klinefelter syndrome and other less common chromosomal abnormalities. Suspicion for Klinefelter syndrome should be particularly high in men with small (especially <6 cc) testes, gynecomastia, learning disorders or behavioral problems, although mosaic Klinefelter syndrome may have much subtler clinical manifestations.

In men with secondary hypogonadism, further evaluation should include:

Transferrin saturation and ferritin - Hypogonadism is the most common endocrine abnormality in men with HH and may be reversible if identified and treated at an early age. The presence of unexplained liver function abnormalities, cardiac dysfunction, diabetes mellitus, and skin hyperpigmentation (in addition to hypogonadism) should raise suspicion for HH.

In men with secondary hypogonadism, further evaluation may include:

Pituitary function testing - If the history and physical exam suggest hypothyroidism or adrenal insufficiency, then a TSH and free T4, and 8 a.m. cortisol (or cosyntropin stimulation testing), should be obtained, respectively.

Pituitary-protocol MRI - Reserved for men with severe testosterone deficiency (e.g., serum total testosterone <50 ng/dL), symptoms or signs of potential tumor or mass effect (e.g., headache, visual loss or field defects, hyperprolactinemia), or evidence of other pituitary hormone loss or excess, especially if there is no obvious cause (e.g., morbid obesity, common offending medications).

Additional studies that are useful in both primary and secondary hypogonadism may include:

Semen analysis - For men interested in fertility. Semen analysis should ideally be collected within 1 hour of ejaculation and after 48-72 hours of abstinence. Given significant intraindividual variability, repeated analyses are frequently needed.

Dual-energy X-ray absorptiometry (DXA) - For men who have sustained fragility fractures, have radiographic osteopenia, or have severely low testosterone levels.

Approach to Treatment of Hypogonadism

Who should be treated?

We recommend treating boys with constitutional delay of puberty, and adult men with consistent signs of symptoms in the presence of overtly low serum testosterone levels. Androgen replacement therapy remains controversial for aging men without classical syndromes, as well as for those with low testosterone levels associated with chronic disease. There is growing data to support the use of androgen replacement in men with HIV and glucocorticoid-induced secondary hypogonadism. Recent data has demonstrated improvement in sexual function in symptomatic older men >65 years of age with mildly low serum testosterone levels, although whether the benefits of treatment outweigh the risks remains unclear.

Over the preceding decade, there has been a nearly four-fold increase in the number of testosterone prescriptions written in the United States, attributed to increased ease of administration coupled with direct-to-consumer advertising. Disturbingly, many of these prescriptions were provided to men with normal testosterone levels, or without prior biochemical evaluation. We strongly recommend against the use of androgen replacement therapy in healthy men with nonspecific symptoms and mild, or single but not consistently low serum testosterone levels. Men who have normal serum testosterone concentrations should not be treated, regardless of symptoms.

In men with secondary hypogonadism who desire fertility, injectable human chorionic gonadotropin (hCG) may be used for induction or maintenance of spermatogenesis and normalization of serum testosterone levels. hCG has the same biologic activity as LH but with the benefit of a longer half-life due to heavier glycosylation, and stimulates testicular Leydig cells to secrete testosterone. Pre-pubertal boys often require administration of both hCG and FSH therapy to restore spermatogenesis; post-pubertal men usually do not require supplemental FSH injections.

Goal of therapy and expected benefits

The goal of androgen replacement therapy is to raise serum testosterone levels to the mid-normal range for young healthy men, and to alleviate symptoms and signs of hypogonadism. Androgen replacement therapy of hypogonadal men has been shown to improve:

Sexual libido

Frequency/duration of spontaneous erections

Hair growth in androgen-sensitive body areas

Muscle mass

Body fat percentage

Muscle strength

BMD

There is suggestion of a benefit of androgen replacement therapy on mood. It is not clear if treatment improves cognition.

Potential adverse effects and contraindications of therapy

Growth of subclinical or metastatic hormone-responsive cancer of the prostate or breast - avoid in men with active prostate or breast cancer, or those with an unevaluated prostate nodule, asymmetric induration, or prostate specific antigen (PSA) >4 ng/L (or >3 ng/L in high risk populations).

Worsening or precipitation of insipient OSA - avoid in men with uncontrolled or untreated severe OSA.

Reduction in sperm quantity and fertility - avoid in men desiring fertility.

Uncontrolled congestive heart failure.

Acne, oily skin.

Male pattern balding.

Gynecomastia.

Drug-drug interactions. Testosterone can enhance the effect of vitamin K antagonists and insulin. Testosterone can also enhance the hepatotoxic effect of systemic cyclosporine, mineralocorticoid effect of systemic corticosteroids, and thrombogenic effect of conestat alfa.

See below for adverse effects specific to each androgen replacement formulation.

Checklist prior to starting therapy

Perform a digital prostate exam in men >40 years of age to exclude nodules or asymmetry, and measure a baseline PSA level. In men >55 years of age, we also recommend use of a prostate cancer risk calculator to estimate risk.

Assess for LUTS (we recommend using the IPSS to quantify symptoms, if the review of systems is positive).

Treatment Regimens and Monitoring

General principles of monitoring

Men treated with androgen replacement should be monitored regularly to ensure target serum testosterone levels and clinical goals are met, and to perform surveillance for adverse effects of therapy. The timing of serum testosterone measurements varies with each specific formulation. The goal serum testosterone level is typically the mid-normal range (>350 ng/dL, <700 ng/dL for most assays).

Check hematocrit; if it increases to >54%, stop therapy until hematocrit decreases into the normal range. Evaluate for OSA or other conditions associated with secondary erythrocytosis. Resume therapy at a lower dose.

Evaluate for adverse effects of testosterone or the testosterone formulation.

Check hematocrit; if it increases to >54%, stop therapy until hematocrit decreases into the normal range. Evaluate for OSA or other conditions associated with secondary erythrocytosis. Resume therapy at a lower dose.

Perform digital rectal examination and check PSA.

Obtain urologic consultation for new prostate abnormalities, an increase in serum PSA of >1.4 ng/mL over a 12-month period, PSA >4 ng/L (or >3 ng/L in high risk populations), or IPSS >19.

Testosterone therapy

We recommend starting with transdermal testosterone formulations due to their convenience, ease of use, and effectiveness in restoring serum testosterone levels into the normal range. Specific formulations should be chosen based on patient preference, insurance coverage, cost, patient comorbidities, and risks associated with each formulation. We suggest switching to an alternative formulation if the goal serum testosterone level is not obtained despite dose titration, or if adverse effects particular to the formulation occur. In general, intramuscular testosterone ester preparations have the lowest out-of-pocket cost.

Transdermal formulations

Gels

Instructions: Follow manufacturer instructions. Androgel®, Testim®, Vogelxo® are applied in the morning to the shoulder and upper arms. Fortesta® is applied to the thighs.

Counseling: Wash hands thoroughly and cover application site with clothing immediately after application.

Monitoring: Serum total testosterone level drawn any time after patient has been on a stable dose for at least two weeks. Most manufacturers vary in their recommendations of the timing of serum testosterone draws in relation to gel application. There is high intra-individual variability of serum testosterone measurements in men treated with gels; at least two values should be obtained before titrating gel doses.

Goal testosterone level: Mid-normal range.

Troubleshooting: For patients who have suboptimal responses to gels, assess for daily adherence and proper application to a sufficiently large surface area. Some patients absorb transdermal gels poorly and should be switched to an alternative formulation if goal serum testosterone levels are not met despite titration to the maximum daily dose.

Adverse effects: Potential risk for transfer to partner or other people in close contact (e.g., children), skin irritation.

N.B. For each gel formulation, the dosage of testosterone is expressed in milligrams while the dosage of the gel carrier is expressed in grams.

Instructions: Patient should be taught to draw up medication, clean the injection site at the vastus lateralis or upper outer quadrant of the gluteus maximus muscles, and inject into the muscle while avoiding vascular structures.

Monitoring: Serum total testosterone level drawn midway between injections (target mid-normal range), or just prior to next dose.

Goal testosterone level: Mid-normal range (if drawn midway between injections), or low-normal range (if drawn as a trough, just prior to next dose)

Adverse effects: Pain, infection, or bleeding at injection site, peak and nadir of mood and/or libido, cough immediately following injection (pathophysiology unclear, but attributed to oil microembolism). Intramuscular testosterone is more likely than other routes to cause erythrocytosis and should be used with caution in men with high-normal hemoglobin values.

N.B. Testosterone enanthate availability has declined in the United States. However, testosterone cypionate is widely available and has similar pharmacokinetics.

Starting dose: 750 mg followed by an additional 750 mg four weeks later, followed by an additional 750 mg 10 weeks later and every 10 weeks thereafter

Titration: Adjust dosing interval rather than dose

Warning: Testosterone undecanoate has a United States boxed warning for serious pulmonary oil microembolism and anaphylaxis). Prescribing must be done through the Aveed® risk management (REMS) program. Patients should receive injections under observation and be monitored for at least 30 minutes after injections.

Pellets

Instructions: Surgically inserted into the subcutaneous tissue by a health-care provider.

Monitoring: Serum total testosterone level drawn at the end of the dosing interval. Examine pellet insertion site at each appointment.

Contraindications: Not recommended for men with sinus disease, mucosal inflammatory disorders, a history of nasal or sinus surgery, recent nasal fracture, or any nasal fracture leading to deformity of the nasal septum. Use has not been established in men with a BMI >35 kg/m2.

Monitoring: Serum total testosterone level drawn after at least four weeks of therapy.

N.B. There are several acceptable hCG administration regimens. The following instructions, starting dose, and titration guidelines are our personal recommendation and represent common practice at our institution.

Instructions: Patient should be taught to inject 10 cc of sterile saline into the hCG vial to yield a 1,000 units/mL suspension.

Monitoring: Serum total testosterone level drawn in the morning before administration (trough level) after the patient has been on a stable dose for one month. Estradiol should also be measured if breast tenderness or overt gynecomastia occurs, or if the serum testosterone level is higher than expected.

Goal testosterone level: Trough level in the low-normal range.

Adverse effects: Pain, infection, or bleeding at injection site. Gynecomastia may occur, particularly if the serum testosterone trough levels are higher than the low-normal range.

Formulations:

hCG: 10,000 units/vial (powder)

Starting dose: 1,000 units subcutaneously every other day

Titration: 500 unit increments; amount of diluent may be reduced to avoid pain from high volume administration